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Opioid Use Disorder (OUD) and opioid-related deaths remain a major public health concern in the United States. Both environmental and genetic factors influence risk for OUD. We previously identified Hnrnph1 as a quantitative trait gene underlying the stimulant, rewarding, and reinforcing properties of methamphetamine. Prior work demonstrates that hnRNP H1, the RNA-binding protein encoded by Hnrnph1, post-transcriptionally regulates Oprm1 (mu opioid receptor gene) – the primary molecular target for the therapeutic and addictive properties of opioids. Because genetic variants can exert pleiotropic effects on behaviors induced by multiple drugs of abuse, in the current study, we tested the hypothesis that Hnrnph1 mutants would show reduced behavioral sensitivity to the mu opioid receptor agonist fentanyl. Hnrnph1 mutants showed reduced sensitivity to fentanyl-induced locomotor activity, along with a female-specific reduction in, and a male-specific induction of, locomotor sensitization following three, daily injections (0.2 mg/kg, i.p.). Hnrnph1 mutants also required a higher dose of fentanyl to exhibit opioid reward as measured via conditioned place preference. Male Hnrnph1 mutants showed reduced fentanyl reinforcement. Hnrnph1 mutants also showed reduced sucrose motivation, suggesting a reward deficit. No genotypic differences were observed in baseline thermal nociception, fentanyl-induced antinociception, physical or negative affective signs of opioid dependence, or in sensorimotor gating. In the context of our prior work, these findings suggest that Hnrnph1 dysfunction exerts a selective role in reducing the addiction liability to drugs of abuse (opioids and psychostimulants), which could provide new biological pathways to improve their therapeutic profiles.
Learn More >Neurological disorders are the leading cause of disability-adjusted life years (DALYs) and the second leading cause of deaths. The four large contributors of neurological DALYs are stroke, migraine, dementia and meningitis [1]. Global and regional actions to decrease this burden are urgently needed. To appropriately set priorities and allocate resources for such actions, political leaders need to be informed by epidemiological and health economic studies.
Learn More >Evidence-based treatment of opioid use disorder, the prevention of opioid overdose and other opioid-related harms, and safe and effective pain management are priorities for the Veterans Health Administration (VHA). The VHA Office of Health Services Research and Development hosted a State-of-the-Art Conference on "Effective Management of Pain and Addiction: Strategies to Improve Opioid Safety" on September 10-11, 2019. This conference convened a multidisciplinary group to discuss and achieve consensus on a research agenda and on implementation and policy recommendations to improve opioid safety for Veterans. Participants were organized into three workgroups: (1) managing opioid use disorder; (2) Long-term opioid therapy and opioid tapering; (3) managing co-occurring pain and substance use disorder. Here we summarize the implementation and policy recommendations of each workgroup and highlight important cross-cutting issues related to telehealth, care coordination, and stepped care model implementation.
Learn More >There is inadequate evidence of long-term benefit from opioid medications for chronic pain and substantial evidence of potential harms. For patients, dose reduction may be beneficial when implemented voluntarily and supported by a multidisciplinary team but experts have advised against involuntary opioid reduction.
Learn More >Many clinicians are reevaluating the use of long-term opioid therapy (LTOT) for chronic pain in response to the opioid crisis and calls from organizations including the Centers for Disease Control & Prevention to limit prescribing of high-dose opioids. However, this practice change is occurring largely in the absence of data regarding patient outcomes. A 2017 systematic review found inconclusive evidence on the impact of LTOT dose reduction and discontinuation on pain severity and function, quality of life, withdrawal symptoms, substance abuse, and adverse effects. This rapid systematic review provides an updated evidence synthesis of patient outcomes following LTOT dose reduction including serious harms such as overdose and suicide.
Learn More >Chronic pain is a significant risk factor for suicidal ideation (SI) and suicidal behavior (SB), including a 20-40% prevalence rate of SI, a prevalence between 5-14% of suicidal attempts (SA), and a doubled risk of death by suicide in patients with chronic pain compared to controls. In most studies, associations between chronic pain and suicidality are robust even after adjusting for the effect of socio-demographics and psychiatric comorbidity, and particularly for depressive conditions. A number of specific conditions that can modulate suicidality risk in patients with chronic pain have been investigated, but there is a need for their more specific characterization. Numerous recent studies have shown that demoralization and Meaning in Life (MiL) constructs affect suicidality, as risk and protective factors, respectively. These constructs have been mainly investigated in patients with somatic illness and in community-dwelling individuals who may present with SI or SB independently of a psychiatric diagnosis of depression. However, a paucity of studies investigated them in suicidal patients affected by chronic pain.
Learn More >Acute medication overuse is prevalent in patients with migraine.
Learn More >To estimate the baseline rates of vascular events among people with migraine.
Learn More >Preclinical studies have reported that sigma-1 receptor antagonists may have efficacy in neuropathic pain states. The sigma-1 receptor is a unique ligand-operated chaperone present in crucial areas for pain control, in both the peripheral and central nervous system. This study assesses the synergistic antihyperalgesic and antiallodynic effect of haloperidol, a sigma-1 antagonist, combined with gabapentin in rats with peripheral neuropathy. Wistar rats male were subjected to chronic constriction injury (CCI) of the sciatic nerve. The effects of systemic administration of gabapentin and the sigma-1 receptor antagonist, haloperidol, were examined at 11 days post-CCI surgery. An analysis of Surface of Synergistic Interaction was used to determine whether the combination's effects were synergistic. Twelve combinations showed various degrees of interaction in the antihyperalgesic and antiallodynic effects. In hyperalgesia, three combinations showed additive effects, four combinations showed supra-additive effects, and three combinations produced an effect limited by the maximum effect. In allodynia, five combinations showed additive effects, two combinations showed supra-additive effects, and five combinations produced antihyperalgesic effects limited by the maximum effect. These findings indicate that the administration of some specific combination of gabapentin and haloperidol can synergistically reduce nerve injury-induced allodynia and hyperalgesia. This suggests that the haloperidol-gabapentin combination can improve the antiallodynic and antihyperalgesic effects in a neuropathic pain model.
Learn More >The TRPA1 ion channel is activated by electrophilic compounds through the covalent modification of intracellular cysteine residues. How non-covalent agonists activate the channel and whether covalent and non-covalent agonists elicit the same physiological responses are not understood. Here, we report the discovery of a non-covalent agonist, GNE551, and determine a cryo-EM structure of the TRPA1-GNE551 complex, revealing a distinct binding pocket and ligand-interaction mechanism. Unlike the covalent agonist allyl isothiocyanate, which elicits channel desensitization, tachyphylaxis, and transient pain, GNE551 activates TRPA1 into a distinct conducting state without desensitization and induces persistent pain. Furthermore, GNE551-evoked pain is relatively insensitive to antagonist treatment. Thus, we demonstrate the biased agonism of TRPA1, a finding that has important implications for the discovery of effective drugs tailored to different disease etiologies.
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